Inactivating mutations and X-ray crystal structure of the tumor suppressor OPCML reveal cancer-associated functions

被引:7
作者
Birtley, James R. [1 ,6 ]
Alomary, Mohammad [2 ]
Zanini, Elisa [2 ]
Antony, Jane [2 ]
Maben, Zachary [1 ]
Weaver, Grant C. [1 ]
Von Arx, Claudia [2 ]
Mura, Manuela [2 ]
Marinho, Aline T. [2 ]
Lu, Haonan [2 ]
Morecroft, Eloise V. N. [2 ,3 ]
Karali, Evdoxia [2 ]
Chayen, Naomi E. [4 ]
Tate, Edward W. [3 ]
Jurewicz, Mollie [1 ]
Stern, Lawrence J. [1 ]
Recchi, Chiara [2 ]
Gabra, Hani [2 ,5 ]
机构
[1] Univ Massachusetts, Med Sch, Dept Pathol, Worcester, MA 01655 USA
[2] Imperial Coll London, Ovarian Canc Act Res Ctr, Dept Surg & Canc, Du Cane Rd, London W12 0NN, England
[3] Imperial Coll London, Dept Chem, Wood Lane, London W12 0BZ, England
[4] Imperial Coll London, Fac Med, Dept Surg & Canc, Computat & Syst Med, London SW7 2AZ, England
[5] AstraZeneca, IMED Biotech Unit, Early Clin Dev, Clin Discovery Unit, Cambridge SG8 6HB, England
[6] UCB Pharma, Bath Rd, Slough SL1 3WE, Berks, England
基金
英国工程与自然科学研究理事会; 美国国家卫生研究院;
关键词
NEURITE OUTGROWTH; OVARIAN-CANCER; METHYLATION; EXPRESSION; PROTEIN; GENE; INTERFACE; BIOMARKER; PROMOTER; DIGLONS;
D O I
10.1038/s41467-019-10966-8
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
OPCML, a tumor suppressor gene, is frequently silenced epigenetically in ovarian and other cancers. Here we report, by analysis of databases of tumor sequences, the observation of OPCML somatic missense mutations from various tumor types and the impact of these mutations on OPCML function, by solving the X-ray crystal structure of this glycoprotein to 2.65 angstrom resolution. OPCML consists of an extended arrangement of three immunoglobulin-like domains and homodimerizes via a network of contacts between membrane-distal domains. We report the generation of a panel of OPCML variants with representative clinical mutations and demonstrate clear phenotypic effects in vitro and in vivo including changes to anchorage-independent growth, interaction with activated cognate receptor tyrosine kinases, cellular migration, invasion in vitro and tumor growth in vivo. Our results suggest that clinically occurring somatic missense mutations in OPCML have the potential to contribute to tumorigenesis in a variety of cancers.
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页数:16
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